Adamantane derivatives, and in some cases adamantanamides, have been described. See for instance Kilburn et al., U.S. Pat. No. 8,053,431B2; WO02004/089415A2 (Novo Nordisk A/S); WO2004/089416A2 (Novo Nordisk A/S); Narula et al., U.S. Pat. No. 4,985,403; Mathonneau, US 2006057083; WO06/119283 (Hunton & Williams LLP); WO08/054144 (Amorepacific Corporation). Adamantanamides are known pharmaceutical agents, and have also recently become useful in cosmetic compositions.
Amides have been made by reacting carboxylic acid chlorides with primary or secondary amines (Schotten-Baumann-type reaction). In the first step an acid chloride reacts with an amine so that an amide is formed, together with a proton and a chloride ion. Addition of a base is required to absorb this acidic proton, or the reaction will not proceed. The name “Schotten-Baumann reaction conditions” is often used to indicate the use of a two-phase solvent system, consisting of water and an organic solvent. The base within the water phase neutralizes the acid, generated in the reaction, while the starting materials and product remain in the organic phase, often dichloromethane or diethyl ether. Having the base in a separate phase prevents the amine reactant from being protonated, which otherwise would be unable to react as a nucleophile.
See e.g. Klug et al., US 2010/0273879; Katsuhiko et al., JP04308558 ABS; Zainab et al., WO2010/117258A1; Asano et al., Amphiphilic Organocatalyst for Schotten-Baumann-Type Tosylation of Alcohols under Organic Solvent Free Condition, Organic Letters, Feb. 9, 2009, Volume 11, No. 8, pages 1757-1759; Harte et al., Synthesis of α-chloroamides in water, Supplementary Information, Tetrahedron Letters, pages 1-6; Harte et al., Synthesis of α-chloroamides in water, Tetrahedron Letters, Jun. 15, 2006, Volume 47, pages 6321-6324; Morita et al., Water-solvent method for tosylation and mesylation of primary alcohols promoted by KOH and catalytic amines, Green Chem., Aug. 11, 2005, Volume 7, pages 711-715; Nakatsuji et al., Water Solvent Method for Esterification and Amide Formation between Acid Chlorides and Alcohols Promoted by Combined Catalytic Amines: Synergy between N-Methylimidazole and N, N, N′, N′-Tetramethylethylenediamine (TMEDA), Adv. Synth. Catal, 2006, Volume 348, pages 2057-2062; Pappas et al., Selective acylation of polyamines with acid anhydrides and acid chlorides in water, Letter in Organic Chemistry, 2010, Volume 7, No. 7, pages 539-541; Sawamura et al., Manufacture of carboxylic acid amides, Japan Kokai Tokkyo Koho, 1992.
Unfortunately, in the case of adamantanamides, the starting adamantane carbonyl chloride is a solid and the reaction requires an organic solvent, the use of which is undesirable: it may be toxic and/or flammable, and, in any event, requires removal at the end of reaction. If the starting adamantane carbonyl chloride is not solubilized, then the reaction takes a long time and is not efficient. Furthermore, the existing processes frequently result in the formation of by-products which also require complicated/labor-intensive removal.